Treatment resistance to antidepressants occurs in up to 20% of major depressions, can result in persistent disabling morbidity, may increase the risk of suicide, but remains surprisingly understudied. The long term objective of this study is to improve the understanding of treatment resistant depression (TRD) so that available treatments can be used more effectively. The first specific aim is to test the reliability of a method to evaluate treatment resistance. No method is available to differentiate "resistance to" from "intolerance of" adequate antidepressant trials. The second specific aim is to determine the acute and long term efficacy of lithium versus placebo augmentation of nortriptyline (NT). No study exists that has systematically followed lithium augmentation (LiAug) responders prospectively. The third specific aim is to compare the acute and long term efficacy of tranylcypromine (TCP) alone versus TCP plus lithium for the patients who fail to respond to LiAug of NT. No study exists that gives patients who failed LiAug the next treatment systematically and then follows them longitudinally. The fourth specific aim is to develop a predictor scale for response to LiAug and TCP for patients with TRD. No method exists to predict response to any antidepressant. The experimental design and specific methods are: 1) assessment of reliability of the McLean Hospital Antidepressant Treatment Record by five psychiatrists using independent interviews and uncondensed records of 20 consecutive in- and outpatients with DSM-III-R, non-psychotic, unipolar depression, with or without melancholia, who had failed one or more antidepressant trials; 2) comparison of the efficacy of a six week trial of lithium versus placebo added to a prospective failed six week trial of NT (N = 100) in outpatients with the same diagnosis as above; 3) comparison of lithium plus TCP 60 mg daily versus placebo plus TCP in a prospective, randomized, eight week trial with the above subjects who failed LiAug of nortriptyline. Subjects will be followed at regular intervals up to three years; and 4) development of a predictive instrument for response to LiAug and TCP using predictor variables and comorbid conditions. The importance of this four part study is that clinicians will be able to use the methods developed to assess treatment resistance; the acute and long term efficacy of LiAug and TCP, and risk of suicide for TRD will be determined; and predictors for LiAug and TCP for TRD will be developed that can improve future TRD research.